Inhibitory affinity modulation of FcγRIIA ligand binding by glycosphingolipids by inside-out signaling
| Autor: | Nandita Bose, Gurpanna Saggu, Myra L. Patchen, Saki Mihori, Cheng Zhu, Zhou Yuan, Xavier Cullere, Clifford A. Lowell, Tanya N. Mayadas, Michael D. Brenner, Koshu Okubo |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Kidney Disease IgG QH301-705.5 Medical Physiology Phosphatase Ligands General Biochemistry Genetics and Molecular Biology Article Glycosphingolipids 03 medical and health sciences Lactosylceramide chemistry.chemical_compound 0302 clinical medicine LYN Receptors FcgRIIA Humans Biology (General) Lyn music Innate immune system music.instrument Activator (genetics) Chemistry Receptors IgG neutrophil leukocyte recruitment Glycosphingolipid Ligand (biochemistry) lactosylceramide Cell biology soluble b-glucan inhibitory signaling 030104 developmental biology SHP-1 Phosphorylation Biochemistry and Cell Biology affinity modulation glomerulonephritis 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Cell reports Cell reports, vol 35, iss 7 Cell Reports, Vol 35, Iss 7, Pp 109142-(2021) |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY The interaction of the human FcγRIIA with immune complexes (ICs) promotes neutrophil activation and thus must be tightly controlled to avoid damage to healthy tissue. Here, we demonstrate that a fungal-derived soluble β-1,3/1,6-glucan binds to the glycosphingolipid long-chain lactosylceramide (LacCer) to reduce FcγRIIA-mediated recruitment to immobilized ICs under flow, a process requiring high-affinity FcγRIIA-immunoglobulin G (IgG) interactions. The inhibition requires Lyn phosphorylation of SHP-1 phosphatase and the FcγRIIA immunotyrosine-activating motif. β-glucan reduces the effective 2D affinity of FcγRIIA for IgG via Lyn and SHP-1 and, in vivo, inhibits FcγRIIA-mediated neutrophil recruitment to intravascular IgG deposited in the kidney glomeruli in a glycosphingolipid- and Lyn-dependent manner. In contrast, β-glucan did not affect FcγR functions that bypass FcγR affinity for IgG. In summary, we have identified a pathway for modulating the 2D affinity of FcγRIIA for ligand that relies on LacCer-Lyn-SHP-1-mediated inhibitory signaling triggered by β-glucan, a previously described activator of innate immunity. In brief Okubo et al. demonstrate that β-glucan binding to the glycosphingolipid lactosylceramide engages a Lyn kinase to SHP-1 phosphatase pathway that reduces FcγRIIA binding propensity for IgG, which suggests FcγRIIA affinity regulation by “inside-out” signaling. The β-glucan-lactosylceramide-Lyn axis prevents FcγRIIA-dependent neutrophil recruitment in vitro and to intravascular IgG deposits following glomerulonephritis. Graphical Abstract |
| Databáze: | OpenAIRE |
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